Francisella tularensis, the causative agent of tularemia, is classified as a Category A biological warfare agent by The Working Group on Civilian Biodefense because of its extreme infectivity, ease of dissemination, and substantial capacity to cause significant illness and death within a short period of time. Although aerosol-initiated F. tularensis infection is considered as the prime choice for a bioterrorist attack, deliberate contamination of drinking water and the food supply could be an alternative means to spread the infection. This approach would be especially attractive to non-state-supported individuals or groups of fanatical terrorists, who do not have the necessary equipment or technical expertise to generate an effective infectious aerosol. Most current research on F. tularensis has used a systemic infection model with the attenuated live vaccine strain (LVS) of F. tularensis. In contrast, very little is known about the pathogenesis of and immunity to virulent F. tularensis infections, especially following ingestion of the pathogen. Moreover, it is unknown whether or not the current live vaccine, F. tularensis LVS, is effective against oral infection with virulent F. tularensis in the event of food- and water- borne outbreaks because the mechanisms of host defense against type A F. tularensis infection initiated via different routes appear to be different. The primary goal of this R21 application in response to PA-03-080, "Biodefense and Emerging Infectious Diseases Research Opportunities", is to develop and characterize a mouse model of oral infection with type A F. tularensis. Specifically, we aim to: 1) characterize the immunopathogenesis of oral infection with type A F. tularensis in mice; 2) determine the susceptibility of immunocompromised hosts to oral infection with type A F. tularensis; and 3) determine the effectiveness of LVS vaccine against oral infection with virulent F. tularensis. The mouse model developed and characterized under this R21 proposal will be a useful tool for future studies on the immune mechanisms of host defense against food- and water- borne tularemia and for the development and evaluation of effective vaccines and immunotherapeutic agents against virulent F. tularensis infection, the long-term objective of our research project. Results from this proposal will also provide valuable preliminary but fundamental information on the immunopathogenesis of oral F. tularensis infection so that future hypothesis-driven studies with more focused research objectives can be designed and developed.